TWI246508B

TWI246508B - 5-(9-acridinylamino)-toluidine compounds

Info

Publication number: TWI246508B
Application number: TW092134177A
Authority: TW
Inventors: Tsann-Long Su; Jang-Yang Chang; Ting-Chao Chou
Original assignee: Academia Sinica
Priority date: 2003-04-04
Filing date: 2003-12-04
Publication date: 2006-01-01
Also published as: US6821983B2; TW200424178A; US20040198765A1

Abstract

This invention relates to 9-anilinoacridine compounds, and more particularly to their synthesis and their use in pharmaceutical compositions for treating diseases. A compound of the following formula (I) wherein, R1 is hydrogen, CORa, or COORa; each of R2, R3 and R4 is, independently, hydrogen, C1-C10 alkyl, or ORb, with the proviso that R2, R3 and R4 cannot all be hydrogen; each of R5 and R6 is, independently, hydrogen, C1-C6 alkyl, ORc, nitro, halo, N(Rc)2, NH(CH2)pN(Rc)2, (CH2)qOH, (CH2)qX, CONHRc, CONH(CH2)qN(Rc)2, SO3Rc, or SO2Rc with the proviso that when R1 is hydrogen and R4 is CH3, R5 and R6 cannot both be hydrogen; and each of m and n, is independently, 0-4; in which Ra is aryl, or C1-C10 alkyl, optionally substituted with oxo; Rb is C1-C10 alkyl; Rc is hydrogen or C1-C10 alkyl; p is 1-5; and q is 1-3.

Description

1246508 玖、發明說明：相關申請案之交互參考本申請案主張2003年4月4曰申請之先前美國臨時申請案 60/460,3 1 1號之優先權，其全部内容以引用方式併入本文。【發明所屬之技術領域】本發明係有關9-苯胺基吖啶化合物，更尤其有關其合成及其用於治療疾病之醫藥組合物之用途。【先前技術】拓樸異構酶II之抑制劑可展現抗腫瘤活性。此等抑制劑中包括9-苯胺基吖啶化合物，如V-(9-吖啶胺基）甲烷楓-間-甲氧基苯胺（m-AMSA)及CI-921(m-AMSA之5-曱基-4-曱基曱醯胺衍生物），兩者均被研究用於治療白血癌及實心腫瘤。例如參見Cain等人，五狀义C㈣cer 1974，10:539及Arlin Ζ·，Ca/icer TVeai. 1983，967及 Baguley 等人，C㈣cer 1984，44:3245及 Denny 等人，MM· Ckm· 1987，30:658。區別該兩種9-苯胺基吖啶之化學特徵為其易於經歷化學上或微粒體上之可逆氧化反應，而獲得醌二亞胺。例如參見 Shoemaker等人，Cancer 1984，44:1939及 Shoemaker等人，ZVwgMeiaZ?· 1982，10:35 〇1246508 发明发明发明发明发明发明发明发明发明发明发明发明发明发明发明发明发明发明发明相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关相关. TECHNICAL FIELD OF THE INVENTION The present invention relates to a 9-anilinoacridine compound, and more particularly to the use thereof and its pharmaceutical composition for treating diseases. [Prior Art] Inhibitors of topoisomerase II exhibit antitumor activity. Among these inhibitors are 9-anilinoacridine compounds such as V-(9-acridinyl)methane maple-m-methoxyaniline (m-AMSA) and CI-921 (m-AMSA 5-) Both mercapto-4-mercaptoamine derivatives, both of which have been studied for the treatment of white blood cancer and solid tumors. See, for example, Cain et al., C., C (4) cer 1974, 10:539 and Arlin Ζ·, Ca/icer TVeai. 1983, 967 and Baguley et al., C (iv) cer 1984, 44: 3245 and Denny et al., MM·Ckm·1987, 30:658. The chemical characteristics of the two 9-anilinoacridines are distinguished by their ease of undergoing a reversible oxidation reaction on a chemical or microparticle to obtain a quinodiimine. See, for example, Shoemaker et al., Cancer 1984, 44: 1939 and Shoemaker et al., ZVwgMeiaZ? 1982, 10:35 〇

Su等人報導一系列之9-苯胺基吖啶展現抗腫瘤活性，但無法形成S昆二亞胺。例如參見Su等人，dm. 乂以oc· C㈣cer 1994, 368 ;美國專利 5,939,428號；丄 Med· C/zem. 1995, 38, 3226-3235 ;及乂 MM. C/zem· 1999, 42, 4147-4748 〇實例包含其中9-胺基經氧或硫原子取代之衍生物，及其中苯胺 O:\88\88601.DOC -6- 1246508 取代基相對於鍵結至吖啶環之9_位置之氮為對位之衍生物。後者化合物中，一系列之3-(吖啶基）胺基巧·羥基甲基苯胺及其乙基胺基甲酸酯衍生物顯示在體内及體外均具有顯著的抗腫瘤活性。【發明内容】一方面，本發明有關式⑴之化合物： R3Su et al. reported that a series of 9-anilinoacridines exhibited antitumor activity but failed to form Squinimide. See, for example, Su et al., dm. oc oc. C (iv) cer 1994, 368; U.S. Patent No. 5,939,428; 丄Med·C/zem. 1995, 38, 3226-3235; and 乂MM. C/zem· 1999, 42, 4147 -4748 Examples of hydrazines include derivatives in which the 9-amino group is substituted by an oxygen or sulfur atom, and the intermediate aniline O:\88\88601.DOC -6- 1246508 substituent is bonded to the 9-position of the acridine ring Nitrogen is a derivative of the para position. Among the latter compounds, a series of 3-(acridinyl)amine-based hydroxymethylaniline and its ethyl urethane derivative show significant antitumor activity both in vivo and in vitro. SUMMARY OF THE INVENTION In one aspect, the invention relates to a compound of formula (1): R3

O:\88\88601.DOC -7- 1246508 δ氣#子、溴離子、碘離子、硫酸根、硝酸根、磷酸根、豕馱根、甲烷磺酸根、三氟乙酸根及乙酸根。類似地，鹽類亦可由陽離子與9-苯胺基十定化合物之負電荷取代基 (如硫酸根）之間形成。適宜陽離子包含鈉離子、鉀離子、鎂離子、鈣離子、及銨陽離子如四曱基銨離子。前藥實例包含酯類及其他醫藥可接受性衍生物，其投藥至個體後，可提供活性之9-苯胺基吖啶化合物。另一方面，本發明提供一種醫藥組合物，其含有有效量之至少一種上述9-苯胺基吖啶及醫藥可接受性載劑。本發明範圍内亦包含含一或多種上述9_苯胺基吖啶化合物之組合物，其可用於治療癌症，及使用此組合物製造供上述用途之醫藥。又另一方面’本發明有關一種治療患有癌症之個體（如人類、哺乳類、狗、貓、馬）之方法，包括對該個體投予有效量之式（I)化合物。該癌症可為人類白血癌、肉瘤、骨肉瘤、淋巴瘤、黑色素瘤、卵巢瘤、皮膚癌、睪丸癌、胃癌、胰癌、腎癌、乳癌、***結直腸癌、頭頸癌、腦瘤、食道癌、膀胱癌、腎上腺皮質癌、肺癌、支氣管癌、子宮内膜癌、子宮頸癌或肝癌。一方面，本發明有關一種合成式（Π)化合物之方法：O:\88\88601.DOC -7- 1246508 δ gas#, bromide, iodide, sulfate, nitrate, phosphate, strontium root, methanesulfonate, trifluoroacetate and acetate. Similarly, a salt may also be formed between a cation and a negatively charged substituent of a 9-anilinodedepine compound (e.g., sulfate). Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetradecylammonium ions. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives which, upon administration to an individual, provide an active 9-anilinoacridine compound. In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of at least one of the above 9-anilinoacridines and a pharmaceutically acceptable carrier. Also included within the scope of the invention are compositions comprising one or more of the above 9-anilinoacridine compounds which are useful in the treatment of cancer, and the use of such compositions to manufacture a medicament for use as described above. In yet another aspect, the invention relates to a method of treating an individual having cancer, such as a human, a mammal, a dog, a cat, a horse, comprising administering to the individual an effective amount of a compound of formula (I). The cancer can be human white blood cancer, sarcoma, osteosarcoma, lymphoma, melanoma, ovarian tumor, skin cancer, testicular cancer, stomach cancer, pancreatic cancer, kidney cancer, breast cancer, prostate colorectal cancer, head and neck cancer, brain tumor, esophagus Cancer, bladder cancer, adrenocortical carcinoma, lung cancer, bronchial cancer, endometrial cancer, cervical cancer or liver cancer. In one aspect, the invention relates to a method of synthesizing a compound of the formula:

O:\88\8860 丨.DOC -10- .1246508 該方法包括使式（III)化合物： h2n^x^Nh2 ⑽ 與式（IV)化合物接觸： (R6)n~〇0〇~(R5)m (IV) 形成式（Π)化合物。R4為CVC1()烷基或〇Rb。R5及r6各獨立為氫、CrC6烷基、〇Rc、硝基、鹵基、n(rc)2、Nh(ch2)pn(rc)2、 (CH2)qOH、（CH2)qX、C〇NHRc、CONH(CH2)pN(RC)2、犯此或 S〇2Re。m及n各獨立為0-4。Ra為芳基或Cl-CiG烷基，其視情況經酮基取代；Rb*Cl-ClG烷基；R。為氫或Ci-CiQ烷基；p 為1-5 ;及q為1-3 ; L為鹵基、〇S〇2R7或〇R7 ;及 R7為烷基、鹵烷基、或視情況經鹵基或硝基取代之芳基。本發明一或多種具體例之細節述於下列說明中。本發明之其他特徵、目的及優點將由下列說明及申請專利範圍更顯而易見。【實施方式】本發明之化合物可使用習知技術合成。較佳者，該等化合物宜自易於獲得之起始物合成。通常本文所述化合物宜經標準有機化學合成法獲得，包含本文反應圖及實例所例 O:\88\88601.DOC -11 - .1246508 示者。反應圖1O:\88\8860 丨.DOC -10- .1246508 This method involves contacting a compound of formula (III): h2n^x^Nh2 (10) with a compound of formula (IV): (R6)n~〇0〇~(R5) m (IV) forms a compound of the formula (Π). R4 is CVC1() alkyl or 〇Rb. R5 and r6 are each independently hydrogen, CrC6 alkyl, 〇Rc, nitro, halo, n(rc)2, Nh(ch2)pn(rc)2, (CH2)qOH, (CH2)qX, C〇NHRc , CONH(CH2)pN(RC)2, commit this or S〇2Re. m and n are each independently 0-4. Ra is an aryl or Cl-CiG alkyl group which is optionally substituted with a keto group; Rb*Cl-ClG alkyl; R. Is hydrogen or Ci-CiQ alkyl; p is 1-5; and q is 1-3; L is halo, 〇S〇2R7 or 〇R7; and R7 is alkyl, haloalkyl or, optionally, halogen A aryl group substituted with a nitro group. The details of one or more specific examples of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Examples] The compounds of the present invention can be synthesized using conventional techniques. Preferably, the compounds are preferably synthesized from readily available starting materials. Generally, the compounds described herein are preferably obtained by standard organic chemical synthesis, including the reaction schemes herein and examples of the examples: O:\88\88601.DOC -11 - .1246508. Reaction diagram 1

以上顯示合成本發明之9-苯胺基吖啶之一例舉反應圖 (R2、R3、R4及Ra之定義參見式；[)。9-吖啶酮13可轉化成化合物14，其在9-位置含有脱離基。該脱離基可為^基、三氟甲烧磺酸根、甲烷磺酸根、甲苯磺酸根或苯氧基。較佳者’ L為氯。吖啶1 8可經由二胺丨6或丨7與丨4縮合而獲得。在對％二胺16之例中，”L”藉任一胺基之親核性取代可獲得、苯胺基吖啶，其中取代基R3相對於鍵結至吖啶環之氮為間位（如1、4、7及1〇)。另一方面，該不稱二胺17可與丨4經由與R4鄰接之胺基反應，獲得、笨胺基吖啶，其中取代基Μ 相對於鍵結至吖啶環之氮為鄰位(如2、5、8及i ”。最後， O:\88\88601.DOC -12- 1246508 9-苯胺基外哈3& ^ 1 ^ 、9及1 2可藉由先使14與硝基苯胺I 5縮口接著使硝基還原成胺基而合成。使1 8與醯基或烷氧羰基之親電子源如YR1(其中” Υ”為可藉胺基置換之脱離基）反應γ獲得衍生化之9-苯胺基，丫啶19。γ可為齒基或RC〇〇_。車乂么者Y為氣。通常，中間物13或14之環取代模式可保留於18或19中。親核4劑為本技*已知且述於本文所述之化學參考書及娜文中，且包含具有共用電子之試劑。脫離基為本技藝已知且為在反應期間可自分子脫離之任何穩定物種（如鹵離子、三氟甲烷磺酸根、烷氧根、烷基硫醇基或胺基）。前述方法中所用之化學品可包含例如溶劑、試劑、觸媒、保護基及去保護基試劑等。上述方法在本文所述步驟之前或之後，亦可額外包含加入或移除適宜保護基之步驟，以最終合成本文所述結構式之化合物。熟知本技藝者將可了解，合成本文化合物之其他方法對本技蝥中一般技藝人士為易於明瞭者。此外，各種合成步驟可以交替順序或次序進行以獲得所需化合物。合成本文所述化合物所用之合成化學轉化及保護基方法（保護及去保護）為本技藝已知且包含例如R· Lar〇ck，當奸亦痛轉光及應，VCH 出版商（1989) ; Τ· W· Greene&P.GM· Wuts，才滅占‘之保邊基，第 2 版，John Wiley andSons(199l);L Fieser 及M. Fieser，身V4含成之㈣j試漱，了〇匕 Wiley and S〇ns(1994);及L. Paquette編輯之芳硪合成試齋歹存全John Wiley and Sons(1995);及其後之版本。 O:\88\8860l.DOC -13- 1246508 為了說明，例舉之化合物4之合成述於反應圖2。化合物 20暴露至亞硫醯氯及催化量之二甲基甲醯胺（Dmf)中，使 9-鋼基及4-綾基分別轉化成對應之氯基及醯氯基。該中間物二氯化合物未單離，但以N，N-二甲基伸乙二胺處理，獲得化合物21 ’其在吖啶環之心位置含有所需醯胺。化合物21 與3,5-二胺基甲苯22縮合獲得9-苯胺基吖啶1，其接著以氯甲酸乙酯轉化成胺基甲酸乙酯4。反應圖2The above shows a reaction scheme for synthesizing one of the 9-anilinoacridines of the present invention (the definitions of R2, R3, R4 and Ra are shown in the formula; [). The 9-acridone 13 can be converted to the compound 14, which contains a leaving group at the 9-position. The leaving group can be a thiol, a trifluoromethanesulfonate, a methanesulfonate, a tosylate or a phenoxy group. Preferably, 'L is chlorine. Acridine 18 can be obtained by condensation of diamine oxime 6 or hydrazine 7 with hydrazine 4. In the case of % diamine 16, "L" is obtained by nucleophilic substitution of any of the amine groups, and the anilino acridine is obtained, wherein the substituent R3 is meta to the nitrogen bonded to the acridine ring (eg, 1, 4, 7 and 1)). On the other hand, the non-diamine 17 can be reacted with hydrazine 4 via an amine group adjacent to R4 to obtain a sulfhydryl acridine wherein the substituent Μ is ortho to the nitrogen bonded to the acridine ring (eg, 2, 5, 8 and i". Finally, O:\88\88601.DOC -12- 1246508 9-aniline-based external ha 3& ^ 1 ^, 9 and 12 can be obtained by first reacting 14 with nitroaniline I 5 condensing and then synthesizing the nitro group to an amine group, and synthesizing γ to obtain a derivative of 18 with an electrophilic source of a mercapto or alkoxycarbonyl group such as YR1 (wherein "”" is a detachment group which can be substituted by an amine group) 9-anilino, acridine 19. γ can be a dentate group or RC〇〇_. Y is a gas. Usually, the ring substitution pattern of the intermediate 13 or 14 can be retained in 18 or 19. The nucleus 4 is known in the art and is described in the chemical references and Navans herein, and includes reagents having a common electron. The cleavage group is known in the art and is any stable from molecular detachment during the reaction. a species (such as a halide, trifluoromethanesulfonate, alkoxide, alkylthiol or amine). The chemicals used in the foregoing methods may include, for example, solvents, reagents, catalysts, Protecting groups and deprotecting groups, etc. The above methods may additionally comprise the step of adding or removing a suitable protecting group before or after the steps described herein to ultimately synthesize a compound of the formula described herein. It will be appreciated that other methods of synthesizing the compounds herein will be readily apparent to those of ordinary skill in the art. In addition, various synthetic steps can be carried out in an alternate sequence or order to obtain the desired compound. Synthetic chemical conversion and protection for the synthesis of the compounds described herein. The base method (protection and deprotection) is known to the art and includes, for example, R. Lar〇ck, when the traitor is also painful and responsive, VCH Publisher (1989); Τ·W·Greene&P.GM· Wuts, Only to eliminate the 'Bao Bianji, 2nd edition, John Wiley and Sons (199l); L Fieser and M. Fieser, V4 contains (4) j test, 〇匕 Wiley and S〇ns (1994); and L Paquette's edited 硪硪硪 John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John John Reaction Figure 2. Compound 20 In the case of sulphur chloride and a catalytic amount of dimethylformamide (Dmf), the 9-steel group and the 4-fluorenyl group are respectively converted into corresponding chlorine groups and sulfonium groups. The intermediate dichloro compound is not separated. However, treatment with N,N-dimethylethylenediamine gives compound 21' which contains the desired guanamine at the heart of the acridine ring. Compound 21 is condensed with 3,5-diaminotoluene 22 to obtain 9- Anilinopyridinium 1, which is subsequently converted to ethyl urethane 4 with ethyl chloroformate. Reaction diagram 2

本發明範圍亦包含一種醫藥組合物，其含有有效量之至 ’種本I明之苯胺基V σ定化合物及醫藥可接受性載劑。又，本發明涵蓋一種對癌症病患投予有效量之至少一種9 -本胺基ρ丫錢合物之方法。，，有效量”代表對&治療之個體賦予治療效果所需之活性9·苯胺基❸定化合物之量。有效1轭圍可自約0.丨毫克/公斤至約500毫克/公斤，如i毫克/ 公斤至約50毫克/公斤。如熟知本技藝者所了解，有效劑量Also included within the scope of the invention is a pharmaceutical composition comprising an effective amount of an anilino V sigma compound and a pharmaceutically acceptable carrier. Further, the present invention encompasses a method of administering an effective amount of at least one 9-amino-amino ruthenium complex to a cancer patient. , an effective amount "represents the amount of active 9·aniline-based compound required to confer a therapeutic effect on the & treated individual. The effective 1 yoke may be from about 0.1 mg/kg to about 500 mg/kg, such as i mg / kg to about 50 mg / kg. As is known to those skilled in the art, effective dosage

O:\88\88601.DOC -14- 1246508 ；人/口療之疾病種類、投藥途徑、輔藥應用及與i他治t處理之共同使用可能性而變。對任何較病患之特定劑置及治療療程將視各種因素而異，包含所用特定化合物 :活n I齡、體重'一般健康狀況、性別、飲食、投藥、排’世速率、藥物組合、疾病嚴重性及歷程、病徵情況病心對疾病、病況或病徵之意向、及治療醫師之判斷。 ”治療”代表對病患投予本文所述之化合物藉以預防、治癒、癒合、緩解、復原、改變、矯正或舒緩任何主要病徵（如發病、進展、轉移)及/或與本文所述疾/病有關之續發病徵。欲實施本發明之方法，具有_或多終苯胺基<咬化合物之組合物可以非經腸道、M 口、經鼻、經直腸、局部或頰内投藥。本文所用之”非經腸道，，代表皮下、皮内、靜脈内、肌肉内、關節内、動脈内、滑液胞内、胸骨内、硬膜下脸内、病灶内、或頭蓋内注射以及任何適宜之灌注技術。無菌注射組合物可為無毒性非經腸道可接受性稀釋劑或 /合劏中之〉谷液或懸浮液，如丨，3 _ 丁二醇之溶液。可用之可接文性載體及溶劑包括甘露糖醇、水、林格氏試劑及等張氯化鈉浴液。此外，傳統上使用固定油作為溶劑或懸浮介質 (如合成之單-或二-縮水甘油酯）。脂肪酸如油酸及其縮水甘油§曰衍生物可用於製備注射劑，亦可用天然之醫藥可接受性油’如橄棍油或篦麻油，尤其其聚氧乙基化之變體。該等油溶液或懸浮液亦可含長鏈醇稀釋劑或分散劑，或羧甲基纖維素或類似分散劑。其他慣用之界面活性劑如Tweens 或Spans或其他類似乳化劑，或慣用以製造醫藥可接受性固O:\88\88601.DOC -14- 1246508; The type of disease, the route of administration, the application of adjuvants, and the possibility of co-use with human treatment. The specific agent treatment and treatment for any patient will vary depending on various factors, including the specific compound used: live n age, weight 'general health status, gender, diet, medication, volley rate, drug combination, disease Severity, course, and condition The intention of the disease to the disease, condition or condition, and the judgment of the treating physician. "Treatment" means administering a compound described herein to a patient to prevent, cure, heal, relieve, restore, alter, correct or relieve any major condition (eg, onset, progression, metastasis) and/or with the disease described herein. Disease-related continued symptoms. To practice the method of the present invention, a composition having a _ or a multi-terminal aniline < bite compound can be administered parenterally, M, nasally, rectally, topically or buccally. As used herein, "parenteral, on behalf of subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial intracellular, intrasternal, subdural, intralesional, or intracapular injections and Any suitable infusion technique. The sterile injectable composition may be a non-toxic parenterally acceptable diluent or a solution of a solution or a suspension, such as a solution of hydrazine, 3 -butanediol. The carrier and the solvent include mannitol, water, Ringer's reagent and isotonic sodium chloride bath. In addition, fixed oils are conventionally used as a solvent or suspension medium (such as synthetic mono- or di-glycidyl ester). Fatty acids such as oleic acid and its glycidol § 曰 derivatives can be used in the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially polyoxyethylated variants thereof. The oil solution or suspension may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or a similar dispersing agent. Other conventional surfactants such as Tweens or Spans or other similar emulsifiers, or customary pharmaceuticals may be used. Receptive solid

O:\88\8860l.DOC Ϊ246508 體液體或其他藥物劑型之生物㈣調配目的。經口投藥之組合物可為任何口服可接受性劑型，包含膠囊、鍵劑、乳液、及水性懸浮液、分散液及溶液。鍵劑之 :中丨貝用之載劑包含乳糖及玉米澱粉。典型上亦添加潤滑劑如硬脂酸鎂。對勝囊劑型經口投藥而言，可用之稀釋劑包含乳糖及乾燥玉求殿粉。當水性懸浮液或乳液經口投樂時’該活性成分可懸浮或溶於與乳化劑或懸浮劑組合之油相：：若需要’可添加特定甜味劑、矯味劑、或著色劑。 =鼻孔命膝或吸人組合物可依據醫藥調配領域已知之技術 ΐ備。例如’該組合物可製備為在食鹽水中之溶液，利用 ^生基醇或其他適宜保存劑、吸收促進劑以增進生物利用，、氣碳及/或本技藝已知之其他溶解劑或分散劑。，活性9-苯胺基Μ化合物之組合物亦劑供直腸投藥。 W ^ ^ 物中之載劑需為"可接受性，，，其意指可與組 2之活性成分相容U較佳可安定活性成分）且對治療之固無害。可使用-或多種溶解劑作為活性+ 朵啡化人物之醫藥賦形劑。其他載劑實例包含膠體二氧化石夕、硬賴鎂、纖維素、月桂基硫酸鈉及D&c黃色#10。曰夂本發明之9-苯胺基，丫咬化合物可藉由—或分析及體内分析預先篩選其治療痒 : 為本技藝者所悉知者。 ’…正工力效。其他方法亦下列特定實例僅用於例示而Μ任何方式用於限制本發O:\88\8860l.DOC Ϊ246508 Biological fluids or other pharmaceutical formulations (4) Purpose of blending. The orally administered composition can be any orally acceptable dosage form comprising a capsule, a key, an emulsion, and an aqueous suspension, dispersion, and solution. Key agent: The carrier for medium mussels contains lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For the oral administration of the capsule type, the diluent used may include lactose and dried jade powder. When the aqueous suspension or emulsion is orally administered, the active ingredient may be suspended or dissolved in an oil phase in combination with an emulsifying or suspending agent: a particular sweetener, flavor, or coloring agent may be added if desired. = Nostril or knee-absorbent compositions may be prepared according to techniques known in the art of pharmaceutical formulation. For example, the composition can be prepared as a solution in saline, using a bio-based alcohol or other suitable preservative, absorption enhancer to enhance bioavailability, gas carbon, and/or other solubilizing or dispersing agents known in the art. The composition of the active 9-anilinoquinone compound is also administered for rectal administration. The carrier in W^^ needs to be "acceptable," meaning that it is compatible with the active ingredient of Group 2, preferably to stabilize the active ingredient) and is not deleterious to the treatment. A pharmaceutically acceptable excipient can be used as the active + flavonoid. Examples of other carriers include colloidal silica dioxide, hard magnesium, cellulose, sodium lauryl sulfate, and D&c yellow #10. 9 The 9-anilino group of the present invention, the bite compound can be pre-screened for treatment of itching by - or analytical and in vivo analysis: as is known to those skilled in the art. ‘...Working and working. Other methods are also used for the purpose of limiting the present invention in any way.

O:\88\88601.DOC -16- 1246508 明揭示之範圍。無需進一步闡釋，相信熟知本技藝者可依據本文之描述，利用本發明至最完全之程度。中文中述及之所有出版品均以引用方式全文併入供參考。實例1· 5-[9-(4-二甲胺基乙基甲醯胺基甲基）吖啶胺基]-間-甲苯胺鹽酸鹽（4’-CONHCH2CH2NMe2-5’-Me-AMT.3HCl 或化合物 1.3HC1)之製備已知之5-甲基吖啶-9-酮-4-甲酸（6.0克，23.7毫莫耳）及含兩滴DMF之亞硫醯氯（15毫升）之混合物溫和回流40分鐘。混合物減壓濃縮且固體殘留物逐次添加至-1 0 °C下之N，N-二甲基伸乙二胺（8·35克，94·8毫莫耳）及三乙胺（26.0毫升）之CHC13(600毫升）溶液中。擾拌30分鐘後，溶液依序以1 〇〇/0 NaHC〇3水溶液（1〇〇毫升χ2)及水洗滌，以Na2S04脫水及減壓蒸發至乾，獲得粗製9-氯-4-甲基吖啶-5-二甲胺基乙基甲醯胺（7.1克，約94%)，其未經純化直接用於下一步驟。於3,5-二胺基甲苯（3.0克，24.8毫莫耳）及4-甲基嗎啉（5.2 毫升，47.2毫莫耳）之Et〇H(120毫升）懸浮液中，在冰浴下，滴加粗製9-氯-4-甲基吖啶-5-二甲胺基乙基甲醯胺（7.1克， 22.6毫莫耳）之CHC13(360毫升）之溶液。在〇°c攪拌1小時後，使溫度升至室溫並繼續攪拌隔夜。反應混合物藉添加乙醇之鹽酸溶液酸化至pH 2。混合物接著真空蒸發至乾且固體殘留物溶於MeOH(600毫升）/CHCl3(200毫升）之混合物中’以活性碳處理並經矽藻土墊過濾。濾液減壓濃縮且固體產物自EtOH結晶，獲得5-[9-(4-二甲胺基乙基甲醯胺基 -5-甲基）4啶胺基]-間-甲苯胺（4，_c〇NHCH2CH2NMe2-O:\88\88601.DOC -16- 1246508 The scope of the disclosure. Without further elaboration, it is believed that those skilled in the art can <RTIgt; </ RTI> use the invention to the fullest extent. All publications mentioned in the Chinese are incorporated by reference in their entirety. Example 1· 5-[9-(4-Dimethylaminoethylformamidomethyl)acridinyl]-m-toluidine hydrochloride (4'-CONHCH2CH2NMe2-5'-Me-AMT. Preparation of 3HCl or Compound 1.3HC1) Mild mixture of known 5-methylacridin-9-one-4-carboxylic acid (6.0 g, 23.7 mmol) and sulfite chloride (15 ml) containing two drops of DMF Reflux for 40 minutes. The mixture was concentrated under reduced pressure and the solid residue was added successively to N,N-dimethylethylenediamine (8.35 g, 94.8 mmol) and triethylamine (26.0 ml) at -10 °C. CHC13 (600 ml) solution. After 30 minutes of stirring, the solution was washed with 1 〇〇/0 NaHC 3 aqueous solution (1 mL χ 2) and water, dried over Na 2 SO 4 and evaporated to dryness under reduced pressure to give crude 9-chloro-4-methyl. Acridine-5-dimethylaminoethylformamide (7.1 g, ca. 94%) was used in the next step without purification. In an ice bath, in a suspension of 3,5-diaminotoluene (3.0 g, 24.8 mmol) and 4-methylmorpholine (5.2 ml, 47.2 mmol) in EtH (120 mL) A solution of crude 9-chloro-4-methylacridine-5-dimethylaminoethylformamide (7.1 g, 22.6 mmol) in CH.sub.3 (360 mL) was then evaporated. After stirring at 〇 °c for 1 hour, the temperature was allowed to rise to room temperature and stirring was continued overnight. The reaction mixture was acidified to pH 2 with a hydrochloric acid solution of ethanol. The mixture was evaporated to dryness EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure and the solid product was crystallized from EtOH to give 5-[9-(4-dimethylaminoethylcarbamido-5-methyl) 4-pyridinyl]-m-toluidine (4, _c 〇NHCH2CH2NMe2-

P\YAN\SPECIFIC ΑΤΙΟΝ\88601 .DOC 1246508 5f-Me-AMT); 6·4克（5 8%); mp 23 9-240°C ;lH NMR (DMSO-d6) δ 2.26 (3H，s，ArMe)，2.73 (3H，s，ArMe)，2.87 (6H，s，NMe2)， 3.44 (2H，t· J=5.5 Hz, CH2)，3.83 (2H，t，/=5.5 Hz，CH2)，6.92 (1H，m，ArH)，6.98 (1H，m，ArH)，7·07 (1H，m，ArH)，7.42 (1H，m，ArH)，7.59 (1H，m，ArH)，7·94 (1H，m，ArH)， 8·21(1Η，m，ArH)，8.58 (1H，m，ArH)，8.92 (1H，m，ArH)， 10·04，10.89及ll·96(各lH，brs，可交換，NH)對C26H29N50· 3HC1.3H20計算值：C，52.84;H，6.48;N，11.85.實測值：C， 52.91.H，6·47;Ν，11.46. 實例2· 3-[9-(4-二甲胺基乙基甲醯胺基-5-甲基)吖啶胺基]-對-甲苯胺鹽酸鹽（4，-CONHCH2CH2NMe2-5’-Me_APT.3HCl 或化合物 2.3HC1)之製備依循合成 4’-C〇NHCH2CH2NMe2-5，-Me-AMT·3HCl之相同程序，自2,4-二胺基甲苯（2_44克，20.0毫莫耳）、粗製9-氯-4-甲基吖啶-5-二甲胺基乙基甲醯胺（6.84克，20.0毫莫耳）及4-曱基嗎啉（4.4毫升；40.0毫莫耳）製備（4’-CONHCH2CH2NMe2-5’-Me-APT.3HC1):產量 5.29克（57%) : mp 228-229^^11 NMR (DMSO-d6) δ 2.32 (3H，s，AfMe)，2.72 (3H，s，ArMe)，2.87 (6H，s，NMe2)，3.42 (2H，d· /=4.3 Hz，CH2)，3·83 (2H，t，3 Hz，CH2)，6·95 (1H，m，J=5.5 Hz，ArH)，7.25 (1H，s，ArH)， 7·26 (1H，d，J=5.5 Hz，ArH)，7.40 (1H，m，ArH)，7.56 (1H，m， ArH)，7_92 (1H，m，ArH)，8.21 (1H，m，ArH)，8·58 (1H，m， ArH)，8.90(1H，m，ArH)，10.04，10.89 及 11.96 (各 1H，brs，可交換，NH)對（：26Η29Ν50·3Η01·3Η20 計算值：C，52.84;H， P:\YAN\SPECIFICATION\88601 DOC -18- 1246508 6.48;N，11.85·實測值：C，53.07; H，6.50;N，11.42. 實例3· 4-[9_(4-二甲胺基乙基甲醯胺基_5_甲基）吖啶胺基】-2-硝基甲苯之製備依循合成 4’-CONHCH2CH2NMe2-5’-Me-AMT.3HCl之相同程序，但改變使用濃HC1替代4-甲基嗎啉作為縮合觸媒，自 4-胺基-2-硝基甲苯（3.38克，22毫莫耳）、粗製9 -氯-4 -甲基口丫啶-5-二甲胺基乙基甲醯胺（6·83克，20.0毫莫耳）及催化量之濃HC1(0.5毫升）製備4-[9-(4-二甲胺基乙基甲醯胺基-5-甲基）吖啶胺基>2-硝基甲苯：產量6.25克（59%) : mp 241-242°C ; NMR (DMSO-d6) δ 2·56及 2·74 (各 3H，s，Me)，2.87及 2·88 (各 3Η，s，NMe2), 3.42 (2H，m，CH2)，3·85 (2H，m，CH2)， 7.43-7.45 (1H，m，ArH)，7·59-7·61 (3H，m，ArH)，7.94 (1H， m，ArH)，8.10 (1H，m，ArH)，8·22 (1H，m，ArH)，8·63 (1H，m， ArH)，8·90(1Η，m，ArH)，10·06及 10.78(各 1H，brs，NH)對 C26H27N503.2HC1.1.5H20計算值：C，5 6·02;Η，5·79;Ν，12·56· 實測值：C，56,31; H，5·90;Ν，12·72· 實例4· 5-[9-(4-二甲胺基乙基甲醯胺基-5-甲基）吖啶胺基】-對-甲苯胺鹽酸鹽（4’_CONHCH2CH2NMe2_5，-Me-AOT.3HCl或化合物 3.3HC1)之製備 4-[9-(4-二曱胺基乙基甲醯胺基-5-甲基）吖啶胺基]-2-硝基甲苯（3.0克，6.6毫莫耳）及i〇〇/0 Pd/C(3.8克）之含濃HC1(12 毫升）之DMF(12毫升）及MeOH(120毫升）混合物在50 psi氫化5小時。混合物經石夕藻土塾過濾，以DMF(10毫升）洗條。混合之濾液及洗液減壓濃縮且殘留物自EtOH結晶獲得 O:\88\88601.DOC -19- 1246508 4’-C〇NHCH2CH2NMe2-5’-Me-AOT.3HCl ; 2.43 克（86%) : mp 2·86 及 2·87(各 3H，s，NMe2)，3·43 及 3.85(各 2H，m，CH2)， 7·02 (1H，m，ArH)，7·27-7·29 (1H，m，ArH)，7.39-7.40 (2H， m，ArH)，7·57 (1H，m，ArH)，7·93 (1H，m，ArH)，8.21 (1H，m， ArH)，8.59 (1H，m，ArH)，8.92 (1H，m，ArH)，9.07 (2H，brs， NH2)，10.09，10.89 及 11.90(各 1H，brs，NH)對 C26H29N5 0.3HC1.2H20計算值：C，54·50;Η，6·33;Ν，12.22.實測值： C，54.71; H，6·42;Ν，12.40. 實例5· {3-[4-(2-二甲胺基-乙基胺基甲醯基）-5-甲基吖咬基胺基卜5-甲基-苯基}-胺基甲酸乙酯（化合物4)之製備氣甲酸乙酯（0.23毫升，2.4毫莫耳）滴加至_丨〇至下之 W-CONHCI^CI^NMedLMe-AMTOaS 毫克；2.0 毫莫耳）之含°比啶（0.32毫升，4.0毫莫耳）之無水DMF(20毫升）懸浮液中。攪拌2小時後，混合物真空蒸發至乾。殘留物以i N HCl/EtOH於冰浴中處理至PH 2並減壓蒸發至乾。固體殘留物自EtOH再結晶，獲得{3-[4-(2-二甲胺基-乙基胺基曱醯基）-5 -曱基-吖啶-9-基胺基]-5 -曱基_苯基}_胺基甲酸乙酯·· 產 i 905 毫克（85%) ; mp 263-264°C ; 4 NMR (DMSO-d6) δ 1·23 (3H，t，J=7.0 Ηζ，Me)，2.26 (3Η，s，Me)，2·73 (3Η，s，Me)， 2.91 (6H，s，NMe2)，3·43 (2H，d，J=5.3 Hz，CH2)，3.82 (2H， </=5·3 Hz，CH2)，4.10 (2H，q，J=6.9 Hz，CH2)，6.86 (1H，s， ArH)，7·29 (1H，s，ArH)，7·42 (1H，m，ArH)，7.46 (1H，s， ArH)，7·59 (1H，m，ArH)，7·93 (1H，s，ArH)，8·12 (1H，m， O:\88\88601.DOC -20- 1246508P\YAN\SPECIFIC ΑΤΙΟΝ\88601 .DOC 1246508 5f-Me-AMT); 6.4 g (5 8%); mp 23 9-240 ° C; lH NMR (DMSO-d6) δ 2.26 (3H, s, ArMe), 2.73 (3H, s, ArMe), 2.87 (6H, s, NMe2), 3.44 (2H, t·J=5.5 Hz, CH2), 3.83 (2H, t, /=5.5 Hz, CH2), 6.92 (1H, m, ArH), 6.98 (1H, m, ArH), 7.07 (1H, m, ArH), 7.42 (1H, m, ArH), 7.59 (1H, m, ArH), 7·94 ( 1H, m, ArH), 8·21 (1Η, m, ArH), 8.58 (1H, m, ArH), 8.92 (1H, m, ArH), 10·04, 10.89 and ll·96 (each lH, brs , exchangeable, NH) calculated for C26H29N50·3HC1.3H20: C, 52.84; H, 6.48; N, 11.85. Found: C, 52.91.H, 6·47; Ν, 11.46. Example 2· 3-[ 9-(4-Dimethylaminoethylformamido-5-methyl)acridinyl]-p-toluidine hydrochloride (4,-CONHCH2CH2NMe2-5'-Me_APT.3HCl or compound 2.3HC1 Preparation according to the same procedure for the synthesis of 4'-C〇NHCH2CH2NMe2-5,-Me-AMT·3HCl, from 2,4-diaminotoluene (2_44 g, 20.0 mmol), crude 9-chloro-4- Is methyl acridine-5-dimethylaminoethylformamide (6.84 g, 20.0 mmol) and 4-mercapto? Preparation of porphyrin (4.4 ml; 40.0 mmol) (4'-CONHCH2CH2NMe2-5'-Me-APT.3HC1): yield 5.29 g (57%): mp 228-229^^11 NMR (DMSO-d6) δ 2.32 (3H, s, AfMe), 2.72 (3H, s, ArMe), 2.87 (6H, s, NMe2), 3.42 (2H, d· /=4.3 Hz, CH2), 3·83 (2H, t, 3 Hz ,CH2),6·95 (1H,m,J=5.5 Hz,ArH), 7.25 (1H,s,ArH), 7·26 (1H,d,J=5.5 Hz,ArH), 7.40 (1H,m ,ArH), 7.56 (1H, m, ArH), 7_92 (1H, m, ArH), 8.21 (1H, m, ArH), 8.58 (1H, m, ArH), 8.90 (1H, m, ArH) , 10.04, 10.89 and 11.96 (each 1H, brs, exchangeable, NH) pair (: 26Η29Ν50·3Η01·3Η20 Calculated value: C, 52.84; H, P:\YAN\SPECIFICATION\88601 DOC -18- 1246508 6.48;N , 11.85·Measured value: C, 53.07; H, 6.50; N, 11.42. Example 3· 4-[9_(4-Dimethylaminoethylcarbamoylamino-5-methyl) acridineamino]- The preparation of 2-nitrotoluene follows the same procedure for the synthesis of 4'-CONHCH2CH2NMe2-5'-Me-AMT.3HCl, but the use of concentrated HC1 instead of 4-methylmorpholine as a condensation catalyst from 4-amino-2 -nitrotoluene (3.38 g, 22 mmol) Preparation of 4-[9-chloro-4-methylperacridin-5-dimethylaminoethylformamide (6.83 g, 20.0 mmol) and catalytic amount of concentrated HC1 (0.5 mL) 4-[9 -(4-dimethylaminoethylformamido-5-methyl) acridineamino>> 2-nitrotoluene: yield 6.25 g (59%): mp 241-242 ° C; NMR (DMSO -d6) δ 2·56 and 2·74 (each 3H, s, Me), 2.87 and 2.88 (each 3Η, s, NMe2), 3.42 (2H, m, CH2), 3·85 (2H, m , CH2), 7.43-7.45 (1H, m, ArH), 7·59-7·61 (3H, m, ArH), 7.94 (1H, m, ArH), 8.10 (1H, m, ArH), 8· 22 (1H, m, ArH), 8.63 (1H, m, ArH), 8.90 (1Η, m, ArH), 10.06 and 10.78 (each 1H, brs, NH) to C26H27N503.2HC1.1.5 H20 calculated value: C, 5 6·02; Η, 5·79; Ν, 12·56· Measured value: C, 56, 31; H, 5·90; Ν, 12·72· Example 4· 5-[ 9-(4-Dimethylaminoethylformamido-5-methyl)acridinyl]-p-toluidine hydrochloride (4'_CONHCH2CH2NMe2_5, -Me-AOT.3HCl or compound 3.3HC1) Preparation of 4-[9-(4-diaminoaminoethylformamido-5-methyl)acridinyl]-2-nitrotoluene (3.0 g, 6.6 mmol) and i〇 A mixture of 〇/0 Pd/C (3.8 g) in EtOAc (12 mL) EtOAc (EtOAc) The mixture was filtered through celite, and washed with DMF (10 mL). The combined filtrate and washings were concentrated under reduced pressure and the residue was crystallised from EtOH to afford O:\88\88601.DOC -19- 1246508 4'-C〇NHCH2CH2NMe2-5'-Me-AOT.3HCl; 2.43 g (86%) : mp 2·86 and 2·87 (each 3H, s, NMe2), 3·43 and 3.85 (each 2H, m, CH2), 7·02 (1H, m, ArH), 7·27-7·29 (1H, m, ArH), 7.39-7.40 (2H, m, ArH), 7.57 (1H, m, ArH), 7.93 (1H, m, ArH), 8.21 (1H, m, ArH), 8.59 (1H, m, ArH), 8.92 (1H, m, ArH), 9.07 (2H, brs, NH2), 10.09, 10.89 and 11.90 (each 1H, brs, NH) calculated for C26H29N5 0.3HC1.2H20: C , 54·50; Η, 6·33; Ν, 12.22. Found: C, 54.71; H, 6·42; Ν, 12.40. Example 5· {3-[4-(2-dimethylamino-B Preparation of ethylaminocarbazyl)-5-methylindoleylamino-5-methyl-phenyl}-carbamic acid ethyl ester (Compound 4) Ethyl formate (0.23 mL, 2.4 mmol) ) dropwise to W-CONHCI^CI^NMedLMe-AMTOaS mg of _丨〇 to the next; 2.0 mM of a suspension containing anhydrous pyridine (0.32 ml, 4.0 mmol) in anhydrous DMF (20 ml) . After stirring for 2 hours, the mixture was evaporated to dryness in vacuo. The residue was taken up in EtOAc (EtOAc) EtOAc. The solid residue is recrystallized from EtOH to give {3-[4-(2-dimethylamino-ethylaminopurinyl)-5-indolyl-acridin-9-ylamino]-5-oxime _ phenyl}- carbamic acid ethyl ester · · i 905 mg (85%); mp 263-264 ° C; 4 NMR (DMSO-d6) δ 1 · 23 (3H, t, J = 7.0 Ηζ, Me), 2.26 (3Η, s, Me), 2.73 (3Η, s, Me), 2.91 (6H, s, NMe2), 3·43 (2H, d, J = 5.3 Hz, CH2), 3.82 ( 2H, </=5·3 Hz, CH2), 4.10 (2H, q, J=6.9 Hz, CH2), 6.86 (1H, s, ArH), 7·29 (1H, s, ArH), 7· 42 (1H, m, ArH), 7.46 (1H, s, ArH), 7.59 (1H, m, ArH), 7.93 (1H, s, ArH), 8·12 (1H, m, O: \88\88601.DOC -20- 1246508

ArH)，8·47(1Η，m，ArH)，8·72 (1H，m，ArH)，9.78 及 9.87(各 1H，brs，2x NH)對 C29H33N5Or2HC1.3H2〇計算值：C， 58·3 9;Η，6·63 ; N，11 ·74·實測值：C，58.25; H，6·20;Ν，11.34. 實例6· {3-[4-(2-二甲胺基-乙基胺基甲醯基）-5_甲基吖啶_、基胺基】-2 -曱基-苯基}-胺基甲酸乙S旨（化合物5)之製備依循合成化合物4之相同程序，自4’-C〇NHCH2CH2NMe2-5’-Me_APT.3HCl(或化合物2.3HC1)(930毫克；2.0毫莫耳）及氣甲酸乙酯（0.23毫升，2.4毫莫耳）製備化合物5:產量858毫克（80%); mp 182-183〇C； lU NMR (DMSO-d6) δ 1.21 (3H5t5/=7.0 Hz5ArH), 8·47 (1Η, m, ArH), 8.72 (1H, m, ArH), 9.78 and 9.87 (each 1H, brs, 2x NH) calculated for C29H33N5Or2HC1.3H2〇: C, 58·3 9;Η,6·63 ; N,11 ·74·Measured: C,58.25; H,6·20;Ν,11.34. Example 6· {3-[4-(2-dimethylamino-ethyl) Aminomethyl hydrazino)-5-methyl acridine _, arylamino]-2-mercapto-phenyl}-carbamic acid ethyl ethane (compound 5) was prepared according to the same procedure as in the synthesis of compound 4, 4'-C〇NHCH2CH2NMe2-5'-Me_APT.3HCl (or compound 2.3HC1) (930 mg; 2.0 mmol) and ethyl formate (0.23 mL, 2.4 mmol). 80%); mp 182-183〇C; lU NMR (DMSO-d6) δ 1.21 (3H5t5/=7.0 Hz5

Me)，2·29 (3H，s，ArMe)，2·73 (3H，s，ArMe)，2·87 (6H，s， NMe2)，3.41 (2H，bds Hz，CH2)，3.82 (2H，brs，CH2)，4.08 (2H，q，/=7.0 Hz，CH2)，7·09 (1H，m，ArH)，7·31 (1H，m， ArH)，7.40 (1H，m，ArH)，7·57 (1H，m，ArH)，7·62 (1H，s， ArH)，7·93 (1H，s，ArH)，8·21 (1H，m，ArH)，8.88 (1H，m， ArH)，9.06，10.05 及 10.81(各 1H，brs，3x NH)對 C29H33N5 0r3HC1.2H20計算值：C，63.01 ;H，6·61; N，11.49·實測值： C，65·23; H，6.53;N，11.71. 實例7· 5-[4-(2-二甲胺基乙基胺基甲醯基）-5_甲基吖啶基胺基卜2-曱基-苯基卜胺基甲酸乙酯（化合物6)之製備依循合成化合物4之相同程序，自4，-CONHCH2CH2NMe2-5f-Me-AOT.3HCl(或化合物 3.3HC1)(110毫克；2.66莫耳）及氣甲酸乙酯（0.30毫升，3· 19毫莫耳）製備化合物6 :產量858毫克（80%) ; mp 131-132°C; 4 NMR (DMSO-d6) δ 1.21 (3H，t，/=7.0 Ηζ，Me)，2·29 (3Η，s，ArMe)，2·73 (3Η，s，ArMe)， O:\88\88601.DOC -21 - 1246508 2.87 (6H，s，NMe2)，3·41 及 3.82(各 2H，bds CH2)，4.08 (2H，q， /=7.0 Hz，CH2)，7.09 (1H，m，ArH)，7·31-7·33 (1H，m，ArH)， 7.38-7.42 (1H，m，ArH)，7.54-7.61 (2H，m，2χΑγΗ)，7·92-7·94 (1H，m，ΑγΗ)，8.18-8·20 (1H，m，ArH)，8·54-8·8·57 (1H，m， ArH)，8·86 (1H，m，ArH)，9.02 (1H，brs，NH)，10.07 (2H，brs， 2xNH)分析值·· C29H33N50r3HC1.3H20)C，H，N· 實例8· 5-[9_(4-甲基）吖啶胺基卜間-甲苯胺鹽酸鹽 (4，-Me-AMT.HCl或化合物7 HC1)之製備依循合成化合物1之相同程序，自3,5-二胺基曱苯（3.90 克，0.20毫莫耳）、4-甲基-9-氯吖啶（4·55克，0.02毫莫耳）及4-甲基嗎啉（4.4毫升，40毫莫耳）合成4、Me-AMT.HCl ··產量 4.27克（61%) ; mp> 290°C ; NMR (DMSO-d6) δ 2·27 (3H， s，Me)，2·84 (3H，s，ArMe)，7·07 (2H，m，ArH)，7.18 (1H，m， ArH)，7.39 (lH，.:m，A;H)，7·48 (1H，m，ArH)，7·8 (1H，m， ArH)，8.02 (1H，m，Αι·Η)，8·23(1Η，m，ArH)，8·29(1Η，m， ArH)，8·68 (1H，m，ArH)，11.40及 12.60 (各 1H，brs，2xNH) 對 C21H19N3 HC 10.13H20計算值·· C，71·63; H，5·80; N，11.93. 實測值：C，71·93; H，5·89;Ν，11.54. 實例9· 5-[9_(4-甲基）吖啶胺基卜對-甲苯胺鹽酸鹽 (4’_Me-APT.HCl或化合物8 HC1)之製備依循合成化合物1之相同程序，自4-二胺基甲苯（2.44克， 20.0毫莫耳）、9-氣-4-甲基吖啶（4.55克，20毫莫耳）及4-甲基嗎啉（4.4毫升，4.0毫莫耳）合成4’-乂卜八？1[.11(：1:產量6.16 克（88%); mp> 280°C; 4 NMR (DMSO-d6) δ 2·37 (3H，s， O:\88\88601.DOC -22- 1246508Me), 2·29 (3H, s, ArMe), 2·73 (3H, s, ArMe), 2·87 (6H, s, NMe2), 3.41 (2H, bds Hz, CH2), 3.82 (2H, Brs,CH2),4.08 (2H,q,/=7.0 Hz,CH2),7·09 (1H,m,ArH),7·31 (1H,m,ArH), 7.40 (1H,m,ArH), 7·57 (1H, m, ArH), 7.62 (1H, s, ArH), 7.93 (1H, s, ArH), 8.21 (1H, m, ArH), 8.88 (1H, m, </ RTI> </ RTI> <RTIgt; 6.53; N, 11.71. Example 7· 5-[4-(2-Dimethylaminoethylaminocarbamimidyl)-5-methylacridinylamino-2-phenyl-phenyl-amino Preparation of ethyl formate (Compound 6) followed by the same procedure as for the synthesis of compound 4 from 4, -CONHCH2CH2NMe2-5f-Me-AOT.3 HCl (or compound 3.3HC1) (110 mg; 2.66 mol) and ethyl formate ( Preparation of compound 6: yield 858 mg (80%); mp 131-132 ° C; 4 NMR (DMSO-d6) δ 1.21. (3H,t, /=7.0 Ηζ,Me) , 2·29 (3Η, s, ArMe), 2.73 (3Η, s, ArMe), O:\88\88601. DOC -21 - 1246508 2.87 (6H, s, NMe2), 3.41 and 3.82 (each 2H, bds CH2), 4.08 (2H, q, /=7.0 Hz, CH2), 7.09 (1H, m, ArH), 7·31-7·33 (1H, m, ArH), 7.38-7.42 (1H, m, ArH), 7.54-7.61 (2H, m, 2χΑγΗ), 7.92-7·94 (1H, m, ΑγΗ ), 8.18-8·20 (1H, m, ArH), 8·54-8·8·57 (1H, m, ArH), 8·86 (1H, m, ArH), 9.02 (1H, brs, NH ), 10.07 (2H, brs, 2xNH) Analytical value ··············· Preparation of 4,-Me-AMT.HCl or Compound 7 HC1) Following the same procedure for the synthesis of Compound 1, from 3,5-diaminoindenylbenzene (3.90 g, 0.20 mmol), 4-methyl-9- Synthesis of chloropyridinium (4.55 g, 0.02 mmol) and 4-methylmorpholine (4.4 ml, 40 mmol) 4. Me-AMT.HCl ·· Yield 4.27 g (61%); mp>290°C; NMR (DMSO-d6) δ 2·27 (3H, s, Me), 2·84 (3H, s, ArMe), 7·07 (2H, m, ArH), 7.18 (1H, m, ArH), 7.39 (lH,.:m,A;H),7·48 (1H,m,ArH),7·8 (1H,m,ArH),8.02 (1H,m,Αι· ),8·23(1Η,m,ArH),8·29(1Η,m,ArH),8·68 (1H,m,ArH), 11.40 and 12.60 (each 1H,brs,2xNH) to C21H19N3 HC 10.13 H20 calculated value · · C, 71 · 63; H, 5 · 80; N, 11.93. Found: C, 71 · 93; H, 5 · 89; Ν, 11.54. Example 9 · 5-[9_(4- Preparation of methyl) acridine amino-p-toluidine hydrochloride (4'_Me-APT.HCl or compound 8 HC1) followed by the same procedure for the synthesis of compound 1, from 4-diaminotoluene (2.44 g, 20.0) Synthesis of 4'-乂巴八?, 9-gas-4-methyl acridine (4.55 g, 20 mmol) and 4-methylmorpholine (4.4 ml, 4.0 mmol). 1[.11(:1: yield 6.16 g (88%); mp> 280 °C; 4 NMR (DMSO-d6) δ 2·37 (3H, s, O:\88\88601.DOC -22- 1246508

ArMe)，2·83 (3H, s，ArMe)，7·08 (1H，m，ArH)，7·30 (1H，m， ArH)，7.37-7.48 (3H，m，ArH)，7·86 (1H，m，ArH)，8.01 (1H， m，ArH)，8.25(2H，m，ArH)，8.61(lH，m，ArH)，11.71& 12.96 (各 1H，brs，可交換，NH)對 C21H19N3 · 1HC1.0.25H20 計算值：C，70·38;Η，5.77;N，11.72·實測值：C，70.98; H， 6.06;N， 11.42· 實例10· 4-(9-吖啶胺基）-2-硝基甲苯之製備依循合成4-[9-(4-二甲胺基乙基甲醯胺基-5-甲基）吖啶胺基]-2-硝基甲苯之相同程序，自4-胺基-2-硝基甲苯（3.35 克，22毫莫耳）及9-氣吖啶（4.27克，20毫莫耳）合成4-(9-吖啶胺基）-2-硝基甲苯：產量6.60克（90%) ; mp> 280 °C ; 4 NMR (DMSO-d6) ]H NMR (DMSO-d6) δ 2.57 (3H5 s, Me), 7.50_7·61 (4H，m，ArH)，8.02-8.05 (2H，m，ArH)，8·00 (1H， m，ArH)，8.16-8.18 (1H，m，ArH)，8.30-8.34 (1H，m，ArH)， 11.70 (1H，brs，NH)對 C2〇H15N3〇2.HC1.1.25H20計算值：C， 61·85;Η，4·80;Ν，10.82.實測值：C，61.57; H，4·65;Ν，10.59· 實例11· 4-[9-(4-甲基）吖啶胺基】-2-硝基甲苯之製備依循合成4-[9-(4-二甲胺基乙基甲醯胺基-5-甲基）吖啶胺基]-2-硝基曱苯之相同程序，自9-氣-4-甲基吖咬（4.57克， 20毫莫耳）及4-胺基-2-硝基甲苯（3·35克，22毫莫耳）合成 4-[9-(4-甲基丫啶胺基]-2-硝基甲苯：產量6.65克（86%); mp> 280〇C； lH NMR (DMSO-d6) δ 2.60 (3H? s, Me), 2.85 (3H，s，Me)，7·41-7·45 (1H，m，ArH)，7.50-7.58 (4H，m，ArH)， 7.89-7.91 (1H，m，ArH)，8·02-8·08 (2H，m，ArH)，8.21-8.24 P:\YAN\SPECIFICATION\88601 DOC -23 - 1246508 (1H，m，ArH)，8.30-8.33 (1H，m，ArH)，8.59-8.61 (1H，m，ArMe), 2·83 (3H, s, ArMe), 7·08 (1H, m, ArH), 7·30 (1H, m, ArH), 7.37-7.48 (3H, m, ArH), 7·86 (1H, m, ArH), 8.01 (1H, m, ArH), 8.25 (2H, m, ArH), 8.61 (lH, m, ArH), 11.71 & 12.96 (each 1H, brs, exchangeable, NH) Calcd for C21H19N3 · 1HC1.0.25H20: C, 70·38; Η, 5.77; N, 11.72. Found: C, 70.98; H, 6.06; N, 11.42 · Example 10· 4-(9- acridinium Preparation of 2-nitrotoluene followed by the same procedure for the synthesis of 4-[9-(4-dimethylaminoethylformamido-5-methyl)acridinyl]-2-nitrotoluene Synthesis of 4-(9-acridinyl)-2- from 4-amino-2-nitrotoluene (3.35 g, 22 mmol) and 9-gas acridine (4.27 g, 20 mmol) Nitrotoluene: Yield 6.60 g (90%); mp > 280 °C; 4 NMR (DMSO-d6) ]H NMR (DMSO-d6) δ 2.57 (3H5 s, Me), 7.50_7·61 (4H, m , ArH), 8.02-8.05 (2H, m, ArH), 8·00 (1H, m, ArH), 8.16-8.18 (1H, m, ArH), 8.30-8.34 (1H, m, ArH), 11.70 ( 1H, brs, NH) Calculated for C2〇H15N3〇2.HC1.1.25H20: C, 61·85; Η, 4·80; Ν, 10.82. Measured value C,61.57; H,4·65;Ν,10.59· Example 11· 4-[9-(4-Methyl)acridinyl]-2-nitrotoluene was prepared according to the synthesis 4-[9-(4 - dimethylaminoethylformamido-5-methyl)acridinyl]-2-nitroindole benzene in the same procedure, from 9-gas-4-methyl sputum (4.57 g, 20 m Synthesis of 4-[9-(4-methylacridinyl)-2-nitrotoluene by 4-amino-2-nitrotoluene (3·35 g, 22 mmol): Yield 6.65克(86%); mp>280〇C; lH NMR (DMSO-d6) δ 2.60 (3H? s, Me), 2.85 (3H, s, Me), 7·41-7·45 (1H, m, ArH), 7.50-7.58 (4H, m, ArH), 7.89-7.91 (1H, m, ArH), 8·02-8·08 (2H, m, ArH), 8.21-8.24 P:\YAN\SPECIFICATION\ 88601 DOC -23 - 1246508 (1H, m, ArH), 8.30-8.33 (1H, m, ArH), 8.59-8.61 (1H, m,

ArH)，11.75 (H，bi*s，NH)對 CnHnNsC^.HCl.OMi^O計算值：C，65·62; H，4.85;N，10.93實測值·· C，65·88; H，4·86;Ν， 10.63. 實例12· 4-[9-(4_曱基)吖啶胺基】-鄰-甲苯胺（4’-Me_AOT.HCl或化合物9)之製備依循合成 4，-CONHCH2CH2NMe2-5f-Me-AOT(或化合物 3) 之相同程序，自4-[9-(4-曱基）吖啶胺基l·2-硝基甲苯（3·〇9 克，9.0毫莫耳）合成4-[9-(4-曱基）吖啶胺基]_鄰-曱苯胺··產量 1.64 克（58%) ; mp> 280°C ; 4 NMR (DMSO-d6) δ 2.36 及 2.78 (各 3Η，s，Me)，7·01 (1Η，s，ArH)，7.28-7.30 (1Η，m， ArH)，7·35 (1H，m，ArH)，7.40-7.44 (1H，m，ArH)，7.42-7.44 (1H，m，ArH)，7·48,7·52 (1H，m，ArH)，7.89-7.91 (1H，m， ArH)，8.01-8.05 (1H，m，ArH)，8.27-8.32 (2H，m，ArH) 8.63-8.63 (1H，m，ArH)，11.71 (1H，brs，NH)對 C21H19 Nr2HC1.0.3H2O計算值：C，64.39; H，5.48;N，10.72實測值：C，64·18; H，5·72;Ν，10.59. 實例13· 5-(9-吖啶胺基）-間_曱苯胺（AMT.HC1或化合物 10.HC1)之製備 9-氯吖啶（4.27克，20毫莫耳）之CHC13(20毫升）溶液在-ίο 至-5 °C滴加至3,5-二胺基曱苯鹽酸鹽（3 ·9〇克，20毫莫耳）及 4-甲基嗎啉（4.4毫升，40毫莫耳）之Me〇H(50毫升）混合物中。攪拌1小時後’溫度升至室溫並繼續攪拌3小時。過濾收集橘色沉澱產物，以EtOH洗滌並自Me〇H/CHCl3再結 P:\YAN\SPECIFICATION\88601 .DOC -24- 1246508 晶，獲得3-(9-吖啶胺基）-(對）-曱笨胺鹽酸鹽，4.85克（85%): mp> 280°C 分解；4 NMR (DMSO-d6) δ 2·26 (3H，s，ArMe)， 6·90 (2H，s，ArH)，6·95 (1H，s，ArH)，7.48 (2H，m，2x ArH)， 8.02(2H，m，2x 4ArH)，8.16(2H，m，x ArH)，8.33 (2H，m，2 x ArH), 10.05 及 11.53(各 1H，brs，可交換，NH)對 C2〇H17 Ν3·2Η(：1·1·75Η2〇計算值：C，59.48; H，5.62;N，10.41 實測值：C，59·58; H，5.61;N，10.02. 實例14· 4-(9-吖啶胺基）-對-甲苯胺（APT.HC1或化合物 11.HC1)之製備依循合成AMT.HC1之相同程序，自2,4-二胺基曱苯（2.44 克，20.0毫莫耳）、9-氣吖啶（4·27克，20.0毫莫耳）及4-甲基嗎啉（4.4毫升，40毫莫耳）合成ATP.HC1或化合物11 :產量 5.7 8^(86%) ： mp> 2 80〇C ; lH NMR (DMSO-d6) δ 2.3 8 (3H, s? Ai*Me)，7·12 (1H，m，ArH)，7·32 (1H，m，ArH)，7.38 (1H，m， Αι*Η)，7·47 (2H，m，2x Αι*Η)，8·01 (2H，m，2x ArH)，8.18 (2H， m，2x ArH)，8.30 (2H，m，2x ArH)，11·49 (1H，brs，可交換， NH)對 C20H17Nr2HC1.2H2O計算值：C，61.54; H，5·42;Ν， 10.07實測值：C，61.76; H，5.75;N，10.38· 實例15· 4-(9-吖啶胺基）-鄰_曱苯胺（AOT.HC1或化合物12) 之製備依循合成 4f-CONHCH2CH2NMe2-5’-Me_A〇T(或化合物 3) 之相同程序，自4-(9-吖啶胺基）-2-硝基甲苯（3.0克，9.1毫莫耳）製備4-(9-吖啶胺基）-鄰-曱苯胺（AOT_HCl或化合物12): 產量 2·0克（73%) : mp 256-25 7°C ; 4 NMR (DMSO-d6) δ 2.29 P:\YAN\SPEC1FICAT1〇N\886〇1 D〇c -25- 1246508 (3H，s，Me)，6.92 (1H，m，ArH)，7.23 (1H，m，ArH)， 7·45-7·49 (2H，m，ArH)，7.99-8.03 (2H，m，ArH)，8.10-8.12 (2H，m，ArH)，8·29-8·31 (2H，m，ArH)，11.56 (3H，brs，NH) 對（：2〇；^17%〇2.1^1.4H20計算值：C，58·90;Η，6·42; N，10.30. 實測值：C，58.96; H，6·13;Ν，10.03· 實例16.培養物中人類腫瘤細胞生長之抑制作用細胞毒性分析。在所有人類腫瘤細胞（亦即結腸ΗΤ-29、鼻咽癌瘤ΗΟΝΕ-1及ΒΜ-1、肝癌瘤Hepa_G2、乳癌瘤ΜΧ-1、胃癌瘤TSGH、腦腫瘤DBTRG、口癌瘤KB、乳癌瘤MCF-7 及MX-1、及T-細胞急性淋巴白血癌CCRF-CEM)之72小時培養物内，藉 Scudiero 等人（Cmc1988，48，4827-4833) 所述之XTT-四唑啉鑕分析，測定化合物對細胞生長之影響。添加吩^7井甲氧硫酸鹽（phenazine methosulfate)-X.TT溶. 液，在37°C歷時6小時後，在微盤讀取機（EL 340 ; Bio-Tek 儀器公司，Winooski，VT)上偵測450及630 nm之吸收度。各化合物使用6至7種濃度。化合物抗腫瘤活性之IC5G及劑量效果關聯性藉使用電腦程式在IBM-PC工作站上藉中間-效率作圖計算（Chou等人，Adv· Enzyme Regul· 1984，22，27-55) 專k，微電腦之劑量-效果分析：ED5Q、LD5Q、相乘作用、拮抗作用、低-劑量危險性、受體-配位體結合及酵素鳶力學之定 f ,· Biosoft: Cambridge，U.K·，1987)。化合物1、2、3、4、5及6對五種人類腫瘤細胞株進行試驗。意外地，所有化合物對至少一種細胞株展現之IC5G均低於已知9-苯胺基吖啶抗腫瘤化合物所試驗者。觀察到之最 O:\88\88601.DOC -26- 1246508 大差異為化合物2與已知受試化合物之一間有1 8倍差異。實例17. CCRF-CEM人類淋巴母細胞白血癌細胞及其藥物抗性亞株之生長抑制作用細胞毒性分析。在CCRF-CEM人類淋巴母細胞白血癌細胞及其藥物抗性亞株之72小時培養物内，藉Scudiero等人 (C㈣ar及以.1 988，48, 4827_4833)所述之XTT-四唑啉鑌分析，測定化合物對細胞生長之影響。添加吩17井甲氧硫酸鹽 (phenazine methosulfate)-XTT溶液，在 37°C 歷時 6小時後，在微盤讀取機（EL 340 ; Bio-Tek儀器公司，Winooski，VT)上偵測450及630 nm之吸收度。各化合物使用6至7種濃度。化合物抗腫瘤活性之IC5〇及劑量效果關聯性藉使用電腦程式在IBM-PC工作站上藉中間-效率作圖計算（Chou等人，Adv· Enzyme ReguL 1984, 22, 27-55) (Chou等人，徵雪廢之漱量-效果分析：ED50、LD5Q、相乘作用、拮抗作用、低-劑量危險性、受體-配位體結合及酵素動力學之定量；^ Cambridge，U.K·，1987)。試驗化合物1及2。意外地，化合物1及2兩者（三鹽酸鹽或游離胺化合物）展現之IC5G均低於已知之受試9-苯胺基吖啶化合物。化合物1及2與長春鹼或紫杉醇均不具交叉抗藥性。實例18.化合物對帶有人類乳癌腫瘤MX-異體移植物之無毛小鼠之抑制作用之化學治療功效體内分析。帶有nu/nu基因之無胸腺無毛小鼠用於人類乳癌腫瘤MX-1異體移植。自查理士河繁殖實驗室獲得Outbred Swiss-背景小鼠。於大部分實驗使用8週齡或更大且體重22 O:\88\8860l.DOC -27- 1246508 克或更重之雄性小鼠。藉i.v,注射經尾靜脈投予藥物。使用側徑器測量長度X寬度X高度（或寬度）而估算腫瘤體積。所用之載體為20微升DMSO於180微升食鹽水中。所有動物研究依據Sloan-Kettering癌症中心國際動物護理及利用協會所 δ忍可之國立健康導引協會就動物護理及利用及方案所做之基準進行。試驗化合物1及2。兩化合物在1〇毫克/公斤或更高劑量下，可有效地使腫瘤體積減小約80%且對宿主具極低毒性。該等結果與已知之受試9-苯胺基吖啶化合物相當或比其更優異。其他具體例然而’需了解在不脫離本發。據此，其他具體例亦落於已描述本發明數種具體例。明精神及範圍内可做各種改質下列申請專利範圍内。一 ' O:\88\8860l 28-ArH), 11.75 (H, bi*s, NH) calculated for CnHnNsC^.HCl.OMi^O: C, 65·62; H, 4.85; N, 10.93 measured value · · C, 65 · 88; H, 4·86;Ν, 10.63. Example 12· 4-[9-(4-Hydryl)acridinyl]-o-toluidine (4'-Me_AOT.HCl or Compound 9) was prepared according to the synthesis 4,- The same procedure for CONHCH2CH2NMe2-5f-Me-AOT (or compound 3), from 4-[9-(4-mercapto) acridineaminol. 2-nitrotoluene (3·〇9 g, 9.0 mmol) Synthesis of 4-[9-(4-indolyl)acridinylamino]-o-anilide: 1.64 g (58%); mp> 280 °C; 4 NMR (DMSO-d6) δ 2.36 and 2.78 (3 Η, s, Me), 7·01 (1Η, s, ArH), 7.28-7.30 (1Η, m, ArH), 7·35 (1H, m, ArH), 7.40-7.44 (1H, m, ArH), 7.42-7.44 (1H, m, ArH), 7·48, 7·52 (1H, m, ArH), 7.89-7.91 (1H, m, ArH), 8.01-8.05 (1H, m, ArH) , 8.27-8.32 (2H, m, ArH) 8.63-8.63 (1H,m,ArH), 11.71 (1H, brs, NH) Calculated for C21H19 Nr2HC1.0.3H2O: C, 64.39; H, 5.48; N, 10.72 Found: C, 64·18; H, 5·72; hydrazine, 10.59. Example 13· 5-(9-Acridineamino)-m-anilide (AMT.H Preparation of C1 or Compound 10.HC1) A solution of 9-chloroacridine (4.27 g, 20 mmol) in CHC13 (20 mL) was added dropwise from -ίο to -5 °C to 3,5-diaminoindole A mixture of hydrochloride (3 · 9 g, 20 mmol) and 4-methylmorpholine (4.4 mL, 40 mmol) in EtOAc (50 mL). After stirring for 1 hour, the temperature was raised to room temperature and stirring was continued for 3 hours. The orange precipitated product was collected by filtration, washed with EtOH and then purified from <RTI ID=0.0>&&&&&&&&&&&&&&&&& - 曱胺 amine hydrochloride, 4.85 g (85%): mp > 280 ° C decomposition; 4 NMR (DMSO-d6) δ 2 · 26 (3H, s, ArMe), 6 · 90 (2H, s, ArH ), 6.95 (1H, s, ArH), 7.48 (2H, m, 2x ArH), 8.02 (2H, m, 2x 4ArH), 8.16 (2H, m, x ArH), 8.33 (2H, m, 2 x ArH), 10.05 and 11.53 (each 1H, brs, exchangeable, NH) for C2〇H17 Ν3·2Η(:1·1·75Η2〇 Calculated values: C, 59.48; H, 5.62; N, 10.41 Found: C, 59·58; H, 5.61; N, 10.02. Example 14· 4-(9-Acridineamino)-p-toluidine (APT.HC1 or Compound 11.HC1) was prepared according to the synthesis of AMT.HC1 The same procedure, from 2,4-diaminoindenylbenzene (2.44 g, 20.0 mmol), 9-gas acridine (4·27 g, 20.0 mmol) and 4-methylmorpholine (4.4 mL, 40 mmol. Synthesis of ATP.HC1 or Compound 11: Yield 5.7 8^(86%): mp> 2 80〇C; lH NMR (DMSO-d6) δ 2.3 8 (3H, s? Ai*Me), 7 ·12 (1H, m, ArH), 7·32 (1H, m, ArH) , 7.38 (1H, m, Αι*Η), 7·47 (2H, m, 2x Αι*Η), 8·01 (2H, m, 2x ArH), 8.18 (2H, m, 2x ArH), 8.30 ( 2H, m, 2x ArH), 11·49 (1H, brs, exchangeable, NH) calculated for C20H17Nr2HC1.2H2O: C, 61.54; H, 5.42; Ν, 10.07 Measured: C, 61.76; 5.75; N, 10.38 · Example 15· 4-(9-Acridineamino)-o-anilinoline (AOT.HC1 or Compound 12) was prepared according to the synthesis of 4f-CONHCH2CH2NMe2-5'-Me_A〇T (or Compound 3) The same procedure was used to prepare 4-(9-acridinyl)-o-anilinoline (AOT_HCl or from 4-(9-acridinyl)-2-nitrotoluene (3.0 g, 9.1 mmol). Compound 12): Yield 2·0 g (73%): mp 256-25 7°C; 4 NMR (DMSO-d6) δ 2.29 P:\YAN\SPEC1FICAT1〇N\886〇1 D〇c -25- 1246508 (3H, s, Me), 6.92 (1H, m, ArH), 7.23 (1H, m, ArH), 7·45-7·49 (2H, m, ArH), 7.99-8.03 (2H, m, ArH ), 8.10-8.12 (2H, m, ArH), 8·29-8·31 (2H, m, ArH), 11.56 (3H, brs, NH) Pair (:2〇;^17%〇2.1^1.4H20 Calculated: C, 58·90; Η, 6·42; N, 10.30. Found: C, 58.96; H, 6·13; Inhibition of the cytotoxicity assay of human tumor cell growth was 10.03 Example 16. · culture. In all human tumor cells (ie, colon ΗΤ-29, nasopharyngeal carcinoma ΗΟΝΕ-1 and ΒΜ-1, liver cancer Hepa_G2, breast cancer ΜΧ-1, gastric cancer TSGH, brain tumor DBTRG, oral cancer KB, breast cancer) XTT-tetrazoline guanidine analysis by Scudiero et al. (Cmc 1988, 48, 4827-4833) in a 72-hour culture of MCF-7 and MX-1, and T-cell acute lymphoblastic white blood cell CCRF-CEM) Determine the effect of the compound on cell growth. Add phenazine methosulfate-X.TT solution, at 37 ° C for 6 hours, in a microdisk reader (EL 340; Bio-Tek Instruments, Winooski, VT) The absorbance at 450 and 630 nm was detected. Each compound used 6 to 7 concentrations. IC5G and dose-effect correlation of antitumor activity of compounds by computer program on intermediate-efficiency mapping calculations on IBM-PC workstations (Chou et al., Adv·Enzyme Regul· 1984, 22, 27-55) Dose-effect analysis: ED5Q, LD5Q, multiplication, antagonism, low-dose risk, receptor-ligand binding, and enzyme 鸢 mechanics f, · Biosoft: Cambridge, UK·, 1987). Compounds 1, 2, 3, 4, 5 and 6 were tested on five human tumor cell lines. Surprisingly, all compounds exhibited less IC5G for at least one cell line than those for known 9-anilinoacridine antitumor compounds. The most observed O:\88\88601.DOC -26- 1246508 The large difference is a 18-fold difference between Compound 2 and one of the known test compounds. Example 17. Growth Inhibition of CCRF-CEM Human Lymphocytes White Blood Cells and Their Drug-Resistant Sub-Strains Cytotoxicity Analysis. In a 72-hour culture of CCRF-CEM human lymphoblastic white blood cells and its drug-resistant sub-strains, X.sub.-T.sub. Analysis determines the effect of the compound on cell growth. The phenazine methosulfate-XTT solution was added and the membrane was detected on a microdisk reader (EL 340; Bio-Tek Instruments, Winooski, VT) after 6 hours at 37 °C. Absorption at 630 nm. Each compound used 6 to 7 concentrations. IC5〇 and dose-effect correlation of antitumor activity of compounds were calculated by intermediate-efficiency mapping on IBM-PC workstations using computer programs (Chou et al., Adv. Enzyme ReguL 1984, 22, 27-55) (Chou et al. , the amount of sputum waste - effect analysis: ED50, LD5Q, multiplication, antagonism, low-dose risk, receptor-ligand binding and enzyme kinetics; ^ Cambridge, UK·, 1987) . Test compounds 1 and 2. Surprisingly, both compounds 1 and 2 (trihydrochloride or free amine compound) exhibited lower IC5G than the known 9-anilinoacridine compound. Compounds 1 and 2 were not cross-resistant to vinblastine or paclitaxel. Example 18. Chemotherapy efficacy of compounds against inhibition of hairless mice bearing human breast cancer tumor MX-allografts In vivo analysis. Athymic hairless mice bearing the nu/nu gene were used for human breast cancer tumor MX-1 allograft. Outbred Swiss-background mice were obtained from the Charles River Breeding Laboratory. Male mice of 8 weeks old or older and weighing 22 O: \88 \ 8860 l. DOC -27 - 1246508 g or more were used in most experiments. By i.v, the injection is administered via the tail vein. Tumor volume was estimated using a side diameter gauge measuring length X width X height (or width). The vector used was 20 microliters of DMSO in 180 microliters of saline. All animal studies were conducted on the basis of animal care and utilization and programs based on the National Health and Guidance Association of the National Animal Care and Use Association of Sloan-Kettering Cancer Center. Test compounds 1 and 2. At a dose of 1 mg/kg or higher, the two compounds are effective in reducing tumor volume by about 80% and are extremely toxic to the host. These results are comparable to or superior to the known 9-anilinoacridine compounds tested. Other specific examples However, it is necessary to understand that it does not deviate from this issue. Accordingly, other specific examples also fall within the specific examples of the invention that have been described. Various modifications can be made within the spirit and scope of the following patents. One ' O:\88\8860l 28-

Claims

I24^(QS34177料利申請案中文申請專利範圍替換本(94年8月）拾、申請專利範圍： 1· 一種下式（I)之化合物， R3I24^(QS34177 material application application Chinese patent application scope replacement (August, 1994) Pickup, patent application scope: 1. A compound of the following formula (I), R3

其中’ R1為氫、C〇Ra或c〇〇Ra ; R2、R3及R4各獨立為氫、Ci_Cig烧基或〇Rb，但以2、r3 及R4不同時為氫； R5及R6各獨立為氫、CrC6烷基、〇RC、硝基、齒基、 (CH2)qX、CONHRe或 CONH(CH2)pN(Rc)2，但當 R1為氫且 R4為CH3時，R5&R6不同時為氫；及 m及η各獨立為〇_4 ; 其中Ra為CVC1()烷基，其視情況經酮基取代；…為Ci_Ci〇烧基；Re為氫或CrCw烧基；p為1-5 ;及q為1-3。 2. 如申請專利範圍第1項之化合物，其中R2、R3及R4之一為 CJ-C6烷基或〇Rb及r2、R3&R4之一為氫。 3. 如申請專利範圍第2項之化合物，其中R1為氫。 4·如申請專利範圍第2項之化合物，其中R1為c〇Ra或 COORa 〇 5·如申請專利範圍第4項之化合物，其中Ra為C1-C4烧基，其 1246508 視情況經酮基取代。 6·如申請專利範圍第2項之化合物，其中R5及R6各為氫、 CpC6烧基、0RC、或 c〇NHR4C〇NH(CH^pN(RC)2，且m 及η獨各獨立為1。 7·如申請專利範圍第6項之化合物，其中RC為Ci-C4烷基及ρ 為2。 8·如申請專利範圍第2項之化合物，其中R2、R3&R4之一為 Ci-C6烷基或〇Rb及Rb為烷基。 9·如申請專利範圍第8項之化合物，其中Rl為c〇Ra或 COOR ’ R為匕-。4烧基，其視情況經酮基取代。 10·如申請專利範圍第8項之化合物，其中R1為氫。 11·如申請專利範圍第8項之化合物，其中R5及R6各為氫、〇1-0：6烧基、〇尺。、或（：〇1^111^或(：〇1^11((：：]^2)1；^(1^^，且瓜及η各獨立為1。 12·如申請專利範圍第η項之化合物，其中化。為(：：1_(：4烷基及ρ 為2 〇 13·如申請專利範圍第2項之化合物，其中r2、…及反4之一為 ch3 或 0CH3 〇 14·如申請專利範圍第13項之化合物，其中Rl為c〇Ra或 COORa 〇 15·如申請專利範圍第14項之化合物，其中Ra為烧基，其視情況經酮基取代。 16·如申請專利範圍第15項之化合物，其中Rl為 COCH2CH2COCH3 或 COOCH2CH3。 O:\88\88601-940805.DOC 1246508 口·如申請專利範圍第16項之化合物，其中以及以6各為氫、 Cl-C6 烧基、〇Rc、或 C〇NHRC 或 C〇NH(CH2)pN(RC)2，且叻及η各獨立為i。 18·如申請專利範圍第17項之化合物，其中Rc為CVC4统基及p 為2 〇丄9·如申請專利範圍第18項之化合物，其中R5為 C〇NH(CH2)2N(CH3)2及 R6為 CH3。 20·如申請專利範圍第19項之化合物，其中…及以6分別估據吖啶環之C-4及C-5位置。 21·如申請專利範圍第20項之化合物，其中該化合物為 {3-[4-(2-一甲胺基-乙基胺基甲醯基）·5 -甲基- π丫。定-9-基胺基]-5-甲基-苯基}_胺基甲酸乙酯或{3-[4_(2_二曱胺基_乙基胺基曱醯基）-5-曱基-吖啶-9-基胺基]-4-甲基-苯基μ胺基甲酸乙酯。 22·如申請專利範圍第13項之化合物，其中Rl為氫。 23_如申請專利範圍第22項之化合物，其中r5及r6各為氣、烧基、ORC、或 c〇NHRC或且叻及η各獨立為1。 24. 如申請專利範圍第23項之化合物，其中rc為Cl_C4燒基及為2 〇 25. 如申請專利範圍第24項之化合物，其中汉5 CONH(CH2)2N(CH3)2及 R6為 CH3。 26. 如申請專利範圍第25項之化合物，其中R5及r6分別佔 W豕吖啶環之C-4及C-5位置。 O:\88\88601-940805.DOC 1246508 27·如申請專利範圍第26項之化合物，其中該化合物為[9_(3_ 月女基-5-甲基-苯基）胺基]_5_甲基^丫 π定甲酸（2-二曱胺基 -乙基）-醯胺或[9-(5-胺基-4-甲基_苯基）胺基]_5-曱基^丫。定-心甲酸（2-二甲胺基-乙基）-醯胺。 28·種用於治療癌症之醫藥組合物，包括有效量之式⑴化合物或其醫藥可接受性鹽及醫藥可接受性載劑。 29.如申凊專利範圍第28項之組合物，其中該化合物為如申請專利範圍第7項之化合物。 3〇·如申請專利範圍第28項之組合物，其中該化合物為如申請專利範圍第13項之化合物。 31.如申請專利範圍第28項之組合物，其中該化合物為如申請專利範圍第21項之化合物。請專利範圍第27項之化合物。Wherein 'R1 is hydrogen, C〇Ra or c〇〇Ra; R2, R3 and R4 are each independently hydrogen, Ci_Cig alkyl or 〇Rb, but 2, r3 and R4 are not hydrogen at the same time; R5 and R6 are each independently Hydrogen, CrC6 alkyl, 〇RC, nitro, dentate, (CH2)qX, CONHRe or CONH(CH2)pN(Rc)2, but when R1 is hydrogen and R4 is CH3, R5&R6 is not hydrogen at the same time And m and η are each independently 〇_4; wherein Ra is CVC1() alkyl, which is optionally substituted by a keto group; ... is Ci_Ci fluorenyl; Re is hydrogen or CrCw alkyl; p is 1-5; And q is 1-3. 2. A compound according to claim 1, wherein one of R2, R3 and R4 is CJ-C6 alkyl or hydrazine Rb and one of r2, R3 & R4 is hydrogen. 3. A compound as claimed in claim 2, wherein R1 is hydrogen. 4. The compound of claim 2, wherein R1 is c〇Ra or COORa 〇5. The compound of claim 4, wherein Ra is a C1-C4 alkyl group, and 1246508 is optionally substituted by a ketone group. . 6. The compound of claim 2, wherein R5 and R6 are each hydrogen, CpC6 alkyl, 0RC, or c〇NHR4C〇NH(CH^pN(RC)2, and m and η are each independently 1 7. A compound according to claim 6 wherein RC is a Ci-C4 alkyl group and ρ is 2. 8. A compound according to claim 2, wherein one of R2, R3 & R4 is Ci-C6 Alkyl or hydrazines Rb and Rb are alkyl groups. 9. A compound according to claim 8 wherein R1 is c〇Ra or COOR 'R is 匕-.4 alkyl, which is optionally substituted by a keto group. A compound according to claim 8 wherein R1 is hydrogen. 11. A compound according to claim 8 wherein R5 and R6 are each hydrogen, 〇1-0:6 alkyl, 〇., or (:〇1^111^ or (:〇1^11((::]^2)1;^(1^^, and melon and η are each independently 1. 12·If the compound of claim n) , wherein: (:: 1_(: 4 alkyl and ρ is 2 〇 13 · as the compound of claim 2, wherein one of r2, ..., and 4 is ch3 or 0CH3 〇14. The compound of the 13th item, wherein R1 is c〇Ra or COORa 〇15. The compound of claim 14, wherein Ra is an alkyl group, which is optionally substituted by a keto group. 16. A compound according to claim 15 wherein R1 is COCH2CH2COCH3 or COOCH2CH3. 88\88601-940805.DOC 1246508 The compound of claim 16 of the patent application, wherein each of the 6 is hydrogen, Cl-C6 alkyl, 〇Rc, or C〇NHRC or C〇NH(CH2)pN ( RC) 2, and 叻 and η are each independently i. 18. The compound of claim 17, wherein Rc is a CVC4 group and p is 2 〇丄9 · a compound of claim 18, wherein R5 is C〇NH(CH2)2N(CH3)2 and R6 is CH3. 20. The compound of claim 19, wherein ... and 6 respectively estimate the positions of C-4 and C-5 of the acridine ring 21) A compound according to claim 20, wherein the compound is {3-[4-(2-monomethylamino-ethylaminocarbamimidyl)·5-methyl-π丫. Ethyl 9-aminoamino]-5-methyl-phenyl}-aminocarboxylate or {3-[4_(2-diamino)ethyl-ethylamino)-5-fluorenyl-hydrazine Pyridin-9-ylamino]-4-methyl-phenylimidocarboxylic acid Ethyl ester. The compound of claim 13 wherein R1 is hydrogen. 23_ The compound of claim 22, wherein r5 and r6 are each a gas, a burnt group, an ORC, or a c〇NHRC or And 叻 and η are each independently 1. 24. The compound of claim 23, wherein rc is a Cl_C4 alkyl group and is 2 〇 25. The compound of claim 24, wherein Han 5 CONH(CH2)2N(CH3)2 and R6 are CH3 . 26. The compound of claim 25, wherein R5 and r6 represent the C-4 and C-5 positions of the W豕 acridine ring, respectively. O:\88\88601-940805.DOC 1246508 27. The compound of claim 26, wherein the compound is [9_(3_月女基-5-methyl-phenyl)amino]_5_methyl ^ 丫 π carboxylic acid (2-diamidino-ethyl)-decylamine or [9-(5-amino-4-methyl-phenyl)amino]]-5-fluorenyl. Ding-cardiacic acid (2-dimethylamino-ethyl)-guanamine. 28. A pharmaceutical composition for treating cancer comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 29. The composition of claim 28, wherein the compound is a compound of claim 7 of the scope of the patent. 3. A composition as claimed in claim 28, wherein the compound is a compound according to claim 13 of the patent application. 31. The composition of claim 28, wherein the compound is a compound of claim 21 of the patent application. Please refer to the compound of item 27 of the patent scope.

癌、胃癌、腦癌、乳癌或白血癌。 34· —種合成式（Π)化合物之方法，如申請專利範圍第28項之組合物，其中該化合物為如申Cancer, stomach cancer, brain cancer, breast cancer or white blood cancer. 34. A method for synthesizing a compound of the formula (,), such as a composition of claim 28, wherein the compound is

該方法包括使式（III)化合物： O:\88\88601-940805.DOC 1246508The method comprises making a compound of formula (III): O:\88\88601-940805.DOC 1246508

與式（ιν)化合物接觸： LContact with compound of formula (ιν): L

(IV) 形成式（IV)化合物；其中：烷基或 ORb ; R5及R6各獨立為氫、CVC6烷基、ORe、硝基、鹵基、 (CH2)qX、CONHRc或 CONH(CH2)pN(Rc)2 ;及 m及η各獨立為0-4 ; 1^為(：1-0：1()烷基，其視情況經酮基取代；111)為<：1-(：1()烷基； Rc為氫或C^-Cw烷基；ρ為1-5 ;及q為1-3 ; L為鹵基、0S02R7或OR7 ;及 R7為烷基、鹵烷基、或視情況經鹵基或硝基取代之芳基。 O:\88\88601-940805.DOC(IV) forming a compound of formula (IV); wherein: alkyl or ORb; R5 and R6 are each independently hydrogen, CVC6 alkyl, ORe, nitro, halo, (CH2)qX, CONHRc or CONH(CH2)pN ( Rc)2; and m and η are each independently 0-4; 1^ is (:1-0:1()alkyl, which is optionally substituted by a keto group; 111) is <:1-(:1( Alkyl; Rc is hydrogen or C^-Cw alkyl; ρ is 1-5; and q is 1-3; L is halo, OS02R7 or OR7; and R7 is alkyl, haloalkyl, or optionally An aryl group substituted by a halogen group or a nitro group. O:\88\88601-940805.DOC